Collagenase is an enzyme normally present in mammals. The enzyme, which is produced in a number of body tissues and cells, degrades collagen, (the major structural protein of connective tissues, such as those in bone, skin, tendon and gingiva) normally during connective tissue remodeling. However, when collagenase, is produced in excessive amounts, then the pathologic destruction of these tissues is the result. This excessive collagenase production has been observed to occur in a number of disease states such as hyperparathyroidism, diabetes, periodontal disease and rheumatoid arthritis. The results of excess collagenolysis are serious and debilitating, such as excessive resorption of bone associated with hyperparathyroidism, the ulceration of the cornea, the destruction of joint tissue associated with rheumatoid arthritis, and the breakdown of the gingival collagen fibers and the bony socket associated with periodontal disease.
In recent years, tetracycline has been advocated as an adjunct in the treatment of periodontal diseases, including chronic periodontitis in the adult (Fasciano and Fazio, Quintessence International, October, #10, 1081-1088 (1981)) and more often, for rapidly progressing juvenile periodontitis (Slots, et al., J. Peridontol, 50, 405-509 (1979)); Genco, et al., J. Dent. Res. 60, Special Issue A, Abstract 872 (1981). Its therapeutic efficacy has been attributed solely to the drug's antimicrobial activity particularly against specific Gram-negative organisms believed to be the cause of these diseases (Genco, J. Periodontol, 52, 545-558 (1981)). Recently, Williams, et al., J. Peridontal Res. , 16, 666-674 (1981) described a significant improvement in periodontal disease in dogs on long-term tetracycline therapy, an effect that did not appear to correlate with expected shifts in the crevicular microflora. Williams, et. al. concluded that the beneficial effect of tetracycline must have resulted from the suppression of a strain of bacteria that was not measured in their study. Similar clinical changes were observed in a limited number of human subjects. Tetracycline therapy in periodontal disease has also been evaluated by Ciancio, J. Periodontol., 43, 155-159 (1976) and Ciancio, et al., J. Periodontol., 51, 531-534 (1980). Kornman & Karl, (1982, J. Periodontol., 53, 604-610) reported that the long-term use of tetracycline was clinically beneficial in patients who did not respond to routine periodontal therapy (debridement by instrumentation). In all of these studies, the only perceived value of tetracyclines is an antibacterial drug.
Diabetes in rats and humans has been found to increase tissue collagenase activity. Evidence for this effect was seen in extracts of gingiva and skin (Ramamurthy and Golub, J. Periodontal Res., 18., 31-39 (1983)) and in cultures of gingival tissue (Ramamurthy, et al., J. Periodontal Res., 9, 199-206 (1974); Golub, et al., J. Dent. Res., 57, 520-525, 1978; Kaplan, et al., J. Dent. Res., 61, Special Issue, 275 (1982)). Unusually severe periodontal disease which occurs during diabetes in man (Finestone and Boorujy, Diabetes, 16, 336-340, 1967; Cianciola, et al., J.A.D.A., 104, 653-660 (1982)) and experimental animals (Bissada, et al., Periodontics., 4, 223 (1966)), reflects accelerated collagen breakdown which could be mediated by the excessive collagenase generated during this systemic disease. It has been suggested that the overgrowth of Gram-negative organisms in the gingival crevice of the diabetic rat could, by generating excessive endotoxin in the area, be the cause of the abnormally high collagenase levels in the gingiva (McNamara et al., Archs. Oral Biol., 27, 217-223 (1982)).
Additionally, it has been reported that tetracycline is effective in the treatment of rheumatoid arthritis (Brown, et al., Comp. Pathol. Zoo Animals, (eds. Montali & Migaki), Smithsonian Institution Press, 259-266 (1980)). Brown's sole rationale for the use of these antibiotics is to eliminate infection of the joint tissues with the "mycoplasma group of microorganisms which he believes is the cause of arthritis. However, there has been heretofore no recognition of the ability of tetracycline to reduce pathologically excessive levels of collagenolytic enzyme(s) (such as collagenase) activity to substantially normal levels.